This highly integrated program is focused on the study of factors influencing discrete regional susceptibility to atherogenesis. The complex interplay of mechanical forces and chemical mediators which impinge on platelet vascular interactions and on cells of the vessel wall and their interaction with the extracellular matrix will be elucidated. Distinct and overlapping signaling pathways will be integrated by genomic and proteomic interrogation of determinants of the balance between susceptibility to and protection from atherosclerosis. Particular attention will be paid to how traditional risk factors, including age, hyperiipidemia and gender condition cell signaling pathways of relevance to inflammation and the cell cycle. In Project 1 the role of COX-2 and mPGES-1, will be assessed. Novel mouse models will delineate their contribution in endothelial, vascular smooth muscle cells, macrophages and cardiomyocytes to cardiovascular function. A priori hypothesis testing will complement unbiased approaches to assess the impact of enzyme disruption on discrete phenotypes and biological networks. In Project 4 the interaction between the ApoE/COX-2/PGl2/IP pathway and the cell cycle will be probed, using cell specific deletions and forced expression of COX-2, deletion, antagonism and stimulation of the IP and by using biophysical approaches to assess differential impact on the extracellular matrix. Finally, in Project 5 we shall examine the effect of gender and hyperiipidemia on the discrete expression of genomic subsets in endothelial cells obtained from regions of the pig aorta susceptible to and protected from atherogenesis. This program will take an integrated approach to the study of humoral and mechanical signaling in vascular cells. Factors that underlie the cell to cell heterogeneity of this interaction are likely to contribute to the focal nature of atherogenesis. Cardiovascular disease continues to be the leading cause of death in the United States. Burgeoning incidence of metabolic syndrome, in both the developed and developing world, suggests that this challenge to public health will grow. Our work will pursue new approaches to understanding atherogenesis, the developmental process of atheromatous plaques, using complex approaches to structural biology, genomics, proteomics and metabolomics.